This program project grant has as its focus clinical-laboratory investigations of new chemotherapeutic approaches for the treatment of human malignacies. New concepts, drugs or therapeutic approaches that arise from laboratory studies, are explored, when approprite in patients with malignant disease. The emphasis of clinical studies are Phase I and II trials, in association with community physicians (CCOP's), and by two larger cooperative groups (Gastrointestinal Tumor Study Group and the Eastern Cooperative Oncology Group). Specific projects include development of second generation antifolates (Project 1), inhibitors of calmodulin as antitumor agents (Project 2), chemotherapy-endocrine interactions (Projects 3), new approaches to regional therapy (Projects 4 and 5), studies of differentiation of squamous cell carcinoma (Project 6), the use of monoclonal antibodies in the diagnosis and possible treatment of acute myeloid leukemia (Project 8) and in melanoma (Project 7), development of sensitive immunoassays for early diagnosis of fungal infections in immunocompromised patients (Project 9), and the use of drug resistant genes to confer resistance of bone marrow stem cells to methotrexate. These projects are closely integrated with the Phase I-II clinical studies proposed in patients with acute leukemia, lymphoma, head and neck cancer, gastrointestinal cancer and in melanoma (Project 11). Integration and collaborations among the projects is achieved by the use fo common technologies (e.g., use of monoclonal antibodies in Projects 7, 8, 9, 10), collaboration among investigators with expertise in certain areas (i.e., projects 1, 3, 4, 5, 6, 10), and by linkage of laboratory programs to clinical investigations; i.e., Project 1 to trials in leukemia, head and neck cancer, and in colorectal cancer; Project 3 with future trials in breast cancer, Project 4 with trials in ovarian cancer, Project 6 with future trials in head and neck cancer. Project 8 with acute leukemia, Project 7 with melanoma trials, Project 9 with acute leukemia trials, and Project 10 with future trials in head and neck cancer and lymphoma. These projects are dependent upon Core functions that provide administrative support and data management and biostatistical support.